Tumor Biology

, Volume 36, Issue 9, pp 6833–6838 | Cite as

Clinical significance of topoisomerase 2A expression and gene change in operable invasive breast cancer

  • Jiang-Hua Qiao
  • De-Chuang Jiao
  • Zhen-Duo Lu
  • Sen Yang
  • Zhen-Zhen Liu
Research Article


This study aims to investigate clinical significance of topoisomerase 2A (TOP2A) expression and TOP2A gene change in operable invasive breast cancer. This is a retrospective analysis, which includes 256 patients diagnosed as operable invasive breast cancer. All postoperational waxed specimens were subjected to resectioning for staining. Estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER-2), KI-67, TOP2A expression, and TOP2A gene changes were detected by immunohistochemistry (IHC) and fluorescent in situ hybridization technique (FISH), respectively. Correlation between TOP2A expression and clinicopathological characteristics was also investigated. Effects of TOP2A protein or gene changes on survival rate were detected. Results indicated that 165 were TOP2A positive (64.5 %), and 31 were gene amplification positive (12.1 %). Positive rate of TOP2A expression showed significant correlations with ER, KI-67, and HER-2. The difference of 5-year overall survival (OS) between TOP2A-positive and TOP2A-negative groups did not reach statistical significance (OS: P = 0.321, 85.9 vs. 79.6 %; disease-free survival [DFS]: P = 0.247, 83.3 vs. 75.3 %). Five-year OS in TOP2A amplification group was 68.8 %, which is lower than deficiency and control group (P > 0.05). Subgroup analysis showed no significant differences of OS and DFS either between TOP2A-positive and TOP2A-negative groups or between TOP2A amplification and control group in population of patients with HER-2 amplification, triple negative breast cancer, or hormone-positive breast cancer. In conclusion, positive rate of TOP2A expression correlates significantly with ER, KI-67, and HER-2. However, prognostic significance of either TOP2A expression or TOP2A gene changes in breast cancer and its various subtypes is limited.


Operable invasive breast cancer Topoisomerase Immunohistochemistry Situ hybridization technique Clinical significance 



This work was supported by a grant from the Henan Science and Technology Bureau (No. 132300410213).

Conflicts of interest



  1. 1.
    Lan J, Huang HY, Lee SW, Chen TJ, Tai HC, Hsu HP, et al. TOP2A overexpression as a poor prognostic factor in patients with nasopharyngeal carcinoma. Tumor Biol. 2014;35(1):179–87.CrossRefGoogle Scholar
  2. 2.
    Zaczek A, Welnicka-Jaskiewicz M, Bielawski KP, Jaskiewicz J, Badzio A, Olszewski W, et al. Gene copy numbers of HER family in breast cancer. J Cancer Res Clin Oncol. 2008;134(2):271–9.CrossRefPubMedGoogle Scholar
  3. 3.
    Sherman-Baust CA, Kuhn E, Valle BL. Shih Iem, Kurman RJ, Wang TL, Amano T, Ko MS, Miyoshi I. A genetically, engineered ovarian cancer mouse model based on fallopian tube transformation mimics human high-grade serous carcinoma development. J Pathol. 2014;233(3):228–37.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Karnes RJ, Cheville JC, Ida CM, Sebo TJ, Nair AA, Tang H, et al. The ability of biomarkers to predict systemic progression in men with high-risk prostate cancer treated surgically is dependent on ERG status. Cancer Res. 2010;70(22):8994–9002.CrossRefPubMedGoogle Scholar
  5. 5.
    Moiseyenko VM, Volkov NM, Suspistin EN, Yanus GA, Iyevleva AG, Kuligina ES, et al. Evidence for predictive role of BRCA1 and Qtubiii in gastric cancer. Med Oncol. 2013;30(2):545.CrossRefPubMedGoogle Scholar
  6. 6.
    Tang J, Deng R, Luo RZ, Shen GP, Cai MY, Du ZM, et al. Low expression of ULK1 is associated with operable breast cancer progression and is an adverse prognostic marker of survival for patients. Breast Cancer Res Treat. 2012;134(2):549–60.CrossRefPubMedGoogle Scholar
  7. 7.
    Mohammed ZM, McMillan DC, Elsberger B, Going JJ, Orange C, Mallon E. Doughty, Edwards J. Comparison of visual and automated assessment of KI-67 proliferation and their impact on outcome in primary operable invasive ductal breast cancer. Br J Cancer. 2012;106(2):383–8.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Cortesi L, Marcheselli L, Guarneri V, Cirilli C, Braghiroli B, Toss A, et al. Tumor size, node status, grading, HER2 and estrogen receptor status still retain a strong value in patients with operable breast cancer diagnosed in recent years. Int J Cancer. 2013;132(2):E58–65.CrossRefPubMedGoogle Scholar
  9. 9.
    Cheang MC, Chia SK, Voduc D, Gao D, Leung S, Snider J, et al. KI-67 index, HER-2 status, and prognosis of patients with luminal B breast cancer. J Natl Cancer Inst. 2009;101(10):736–50.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Goldhirsch A, Winer EP, Coates AS, Gelber RD, Piccart-Gebhart M, Thurlimann B, et al. Panel members. Personalizing the treatment of women with early breast cancer: highlights of the St Gallen international expert consensus on the primary therapy of early breast cancer 2013. Ann Oncol. 2013;24:2206–23.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Treszezamsky AD, Kachnic LA, Feng Z, Zhang J, Tokadjian C, Powell SN. BRCA1- and BRCA2-deficient cells are sensitive to etoposide-induced DNA double-strand breaks via topoisomerase-II. Cancer Res. 2007;67(15):7078–81.CrossRefPubMedGoogle Scholar
  12. 12.
    Brase JC, Schmidt M, Fischbach T, Sultmann H, Bojar H, Koelbl H, et al. ERBB2 and TOP2A in breast cancer: a comprehensive analysis of gene amplification, RNA levels, and protein expression and their influence on prognosis and prediction. Clin Cancer Res. 2010;16:2391–401.CrossRefPubMedGoogle Scholar
  13. 13.
    Romero A, Martín M, Cheang MC, Lopez-Asenjo JA, Oliva B, He X, et al. Assessment of topoisomerase II status in breast cancer by quantitative PCR, gene expression microarrays, immunohistochemistry, and fluorescence in situ hybridization. Am J Pathol. 2011;178(4):1453–60.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Fountzilas G, Valavanis C, Kotoula V, Eleftheraki AG, Kalogeras KT. HER2 and TOP2A in high-risk early breast cancer patients treated with adjuvant epirubicin-based dose-dense sequential chemotherapy. J Transl Med. 2012;10(1):10.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    O’Malley FP, Chia S, Tu D, Shepherd LE, Levine MN, Bramwell VH, et al. Topoisomerase II and responsiveness of breast cancer to adjuvant chemotherapy. J Natl Cancer Inst. 2009;101(9):644–50.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Bhargava R, Lal P, Chen B. HER-2/neu and topoisomerase II_ gene amplification and protein expression in invasive breast carcinomas: chromogenic in situ hybridization and immunohistochemical analyses. Am J ClinPathol. 2005;123(6):889–95.Google Scholar
  17. 17.
    Park K, Han S, Gwak GH, Kim HJ, Kim J, Kim KM. Topoisomerase II-gene deletion is not frequent as its amplification in breast cancer. Breast Cancer Res Treat. 2006;98(3):337–42.CrossRefPubMedGoogle Scholar
  18. 18.
    Zaczek AJ, Markiewicz A, Seroczynska B, Skokowski J, Pienkowski T, Olszewski WP, et al. Prognostic significance of TOP2A gene dosage in HER-2-negative breast cancer. Oncologist. 2012;17(10):1246–55.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Wang YX, Fan Y, Zhang Q. Expression of topomerase IIα protein in different molecular subtypes of breast cancer and their prognostic values. Chin J Clin Oncol. 2012;39(7):382–7.Google Scholar
  20. 20.
    Fountzilas G, Christodoulou C, Bobos M, Kotoula V, Eleftheraki AG, Xanthakis I, et al. Topoisomerase II alpha gene amplification is a favorable prognostic factor in patients with HER2-positive metastatic breast cancer treated with trastuzumab. J Transl Med. 2012;10(1):212.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Engstrøm MJ, Ytterhus B, Vatten LJ, Opdahl S, Bofin AM. TOP2A gene copy number change in breast cancer. J ClinPathol. 2014;67(5):420–5.Google Scholar
  22. 22.
    Panousis D, Patsouris E, Lagoudianakis E, Pappas A, Kyriakidou V, Voulgaris Z, et al. The value of TOP2A, EZH2 and paxillin expression as markers of aggressive breast cancer: relationship with other prognostic factors. Eur J Gynaecol Oncol. 2011;32(2):156–9.PubMedGoogle Scholar
  23. 23.
    Liu F, Liu Y, He C, Tao L, He X, Song H, et al. Increased MTHFD2 expression is associated with poor prognosis in breast cancer. Tumor Biol. 2014;35(9):8685–90.CrossRefGoogle Scholar
  24. 24.
    Mrklić I, Pogorelić Z, Ćapkun V, Tomic S. Expression of topoisomerase II-α in triple negative breast cancer. Appl Immunohistochem Mol Morphol. 2014;22(3):182–7.CrossRefPubMedGoogle Scholar
  25. 25.
    Martin M, Romero A, Cheang MC, Lopez-Garcia-Asenjo JA, Garcia-Saenz JA, Oliva B, et al. Genomic predictors of response to doxorubicin versus docetaxel in primary breast cancer. Breast Cancer Res Treat. 2011;128(1):127–36.CrossRefPubMedGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2015

Authors and Affiliations

  • Jiang-Hua Qiao
    • 1
  • De-Chuang Jiao
    • 1
  • Zhen-Duo Lu
    • 1
  • Sen Yang
    • 2
  • Zhen-Zhen Liu
    • 1
  1. 1.Department of Breast surgery, Breast Cancer Center, Affiliated Cancer Hospital of Zhengzhou UniversityHenan Cancer HospitalZhengzhouChina
  2. 2.China-US (Henan) Hormel Cancer Institute, Affiliated Cancer Hospital of Zhengzhou UniversityHenan Cancer HospitalZhengzhouChina

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